We plan to determine the structures of natural products from marine origin by single crystal X-ray diffraction. The compounds will be isolated from marine invertebrates, and marine microorganisms by Drs. F.J. Schmitz and M. Alam. The emphasis will be on compounds which are highly cytotoxic or active in mechanism based assays and those which are active as antitumor agents against slow growing tumors. In addition the structures of marine macrolides and polyethers isolated and identified in other laboratories will be determined by X-ray diffraction in order to improve the knowledge of the 3-d structure of highly active compounds. Also structure with novel chemical features where spectroscopic techniques are inadequate will be determined. the marine macrolides which act as modulators for PKC as one group and the polyethers which act as inhibitors for protein phosphatase (I and IIa) as another group will be analyzed by a detailed methodology in order to identify the pharmacophoric groups or pharmacophore responsible for their interaction with these enzymes. Docking experiments are planned as well at the time the 3-d structure of the enzymes are known. Another project involves the structure investigation of newly synthesized Analog II antiestrogens based on tamoxifen and 1,1-dichloro, cis 2,3 diphenyl cyclopropane. The compounds are synthesized by Dr. R. Magarian. Specifically these compounds fall in six groups: 1) triaryldichloro cyclopropanes (DTAC), 2) metabolites of DTAC's, 3) analogs of MER25 and isolated optical isomers, 4) methylchloro and monochloro cyclopropanes, 5) spiro derivatives of Analog II, and 6) triarylfuran analogs of tamoxifen. All conformations for the compounds will be explored by molecular mechanics to understand the molecular features responsible for their antiestrogenic activity.